It has been recognized that elevated levels of cholesterol in the blood plasma are a major risk factor of coronary heart disease in humans and that reducing plasma cholesterol level decreases the risk of coronary heart disease. Successful approaches to controlling blood cholesterol levels have included dietary modification, e.g., minimizing the intake of cholesterol-laden foods and of foods having high fat content, inhibiting cholesterol biosynthesis and encouraging an increase in the amount of bile acids eliminated by the body.
Particulate resins, e.g., cholestyramine, described in U.S. Pat. No. 3,383,281, and colestipol, described in U.S. Pat. No. 3692895, that are capable of sequestering bile acids are known. Such resins, when orally administered to a mammalian host, form complexes with bile acid conjugates in the intestine and are effective in blocking resorbtion of bile acids from the intestine. The resin and sequestered bile acids are subsequently excreted from the body in fecal matter thereby increasing the rate at which bile acids are eliminated from the body. Other factors being equal, an increase in the rate at which bile acids are eliminated front the body tends to lower plasma cholesterol level by accelerating the conversion of cholesterol to bile acids in order to maintain a constant supply of bile acids in the body. A portion of the cholesterol for this increased synthesis of bile acids is supplied by removal of cholesterol from the blood plasma.
The bile acid sequestrants may be orally administered in various forms, typically as mixtures with food. Although the dosages of known sequestrants that are effective in lowering serum cholesterol in humans typically fall in the range of 10 to 15 grams/day, dosages of up to about 50 grams/day may be required. The particulate bile acid sequestrant resins can be unpleasant to ingest, particularly when large dosages are required and adverse side reactions (bloating, gas formation, constipation, diarrhea and the like) are common among patients to whom the resins are administered.
There has been a continuing effort in this field to minimize the unpleasant side effects associated with a therapeutically effective bile acid sequestrant regimen by developing sequestrants having increased ability to sequester bile acids and which are also effective in reducing serum cholesterol when administered at lower dosages than presently required using cholestyramine and colestipol.
While new candidate bile acid sequestrants must possess satisfactory bile acid sequestering efficacy, they must also be non-toxic to the host receiving the treatment. Some bile acid sequestrants may possess satisfactory bile acid sequestering efficacy, e.g., water-soluble polymers, however, they have been found to be cytotoxic towards the host due to sensitivity of living tissue exposed to the water-soluble bile acid sequestrant. It is, therefore, desirable to provide a bile acid sequestrant that possesses the bile acid sequestering efficacy of such water-soluble polymers but without the cytotoxic side effects which occur due to intimate contact between the sequestrant used and the living tissues exposed to the sequestrant.
One approach to providing bile acid sequestrants having the proper combination of physical properties is to polymerize functionalized monomers which are water-soluble due to their functionalized nature and to crosslink the polymer to such an extent to render it water-insoluble, thus minimizing cytotoxic effects, without hindering accessibility of the functionalized sites of the sequestrant to target bile acids to be removed.
It is an object of the present invention to provide a bile acid sequestrant with enhanced bile acid sequestering efficacy and low mammalian cytotoxicity based on a crosslinked polymer made front functionalized water-soluble monomers. Another object of the invention is to provide a process for preparing the bile acid sequestrant polymer particles, preferably as spherical polymer particles.